KR20060044681A - Microfluidic analytical system with position electrodes - Google Patents

Abstract

Microfluidic analysis systems for monitoring analyte (eg, sugar) in a liquid sample (i.e., ISF) measure at least one micro-channel for receiving and transporting a liquid sample and measuring the sample in the liquid sample. And at least one analyte sensor, at least one position electrode. The sample sensor (s) and position electrode (s) are in operative communication with the micro-channels. The microfluidic system also includes a meter for measuring the electrical properties (such as impedance, resistance) of the position electrode (s). In addition, the measured electrical properties depend on the position of the liquid specimen in the micro-channels in operative communication with the position electrode where the electrical properties are measured.

Microfluidic Analysis System, Micro-Channel, Branch, Position Electrode, Analytical Sample Sensor

Description

Microfluidic analysis system with position electrode {MICROFLUIDIC ANALYTICAL SYSTEM WITH POSITION ELECTRODES}

1 is a schematic cross-sectional view and conceptual view of a microfluidic analysis system according to an embodiment of the present invention.

FIG. 2 is a schematic diagram of a molded plug of the microfluidic analysis system of FIG. 1. FIG.

3 is a schematic top plan view of a micro-channel disk in the microfluidic analysis system of FIG.

4 is a schematic bottom plan view of a laminate layer in the microfluidic analysis system of FIG.

5 is a schematic block diagram illustrating a system in which an embodiment of a microfluidic analysis system according to the present invention can be used to extract a liquid sample from a body and monitor an analyte in the sample.

FIG. 6 shows that the dashed arrows indicate mechanical interaction, while the solid arrows indicate ISF flow, or pressing force when any member 228 is involved, with FIG. 5 being applied to the epidermal layer of the user. Conceptual diagram for the sampling module.

7 is a conceptual diagram of a configuration of a position electrode and a micro-channel, an analyte sample sensor, and a measuring instrument used in an embodiment of a microfluidic analysis system according to the present invention.

8A is a schematic cross-sectional view and a conceptual diagram illustrating the manner in which a position electrode can be disposed in a micro-channel in an embodiment of a microfluidic analysis system according to the present invention.

8B is a schematic cross-sectional view and a conceptual diagram showing how the position electrode is separated from the micro-channel by insulating the epidermal layer in an embodiment of the microfluidic analysis system according to the present invention.

FIG. 9 shows the configuration of different position electrodes and micro-channels, analyte sensors, and meter arrangements used in the implementation of a microfluidic analysis system in accordance with the present invention showing the manner in which the position detector may be in electrical communication with an analyte sensor. schematic.

10 is a schematic diagram of another position electrode and micro-channel, analyte sample, meter configuration used in an embodiment of a microfluidic analysis system according to the present invention, illustrating the use of three position electrodes.

11 is a schematic diagram of a configuration of a position electrode used in an embodiment of a microfluidic analysis system according to the present invention, a main microchannel, a branch microchannel, an analytical sample sensor, and a measuring instrument;

12 is a schematic diagram of the configuration of different position electrodes and main micro-channels, branch micro-channels, analyte samples, and meter used in embodiments of the microfluidic analysis system according to the present invention.

Figure 13 is a schematic diagram of the configuration of the position sensor and the micro-channel, the meter used in the embodiment of the microfluidic analysis system according to the present invention.

14 is a schematic diagram of an equivalent electrical circuit for part of the configuration of FIG. 13.

Figure 15 is a schematic diagram of additional position electrode, micro-channel, meter configuration used in an embodiment of a microfluidic analysis system according to the present invention.

FIG. 16 is a schematic diagram of an equivalent electrical circuit for part of the configuration of FIG. 15. FIG.

Figure 17 is a schematic diagram of a different position electrode, micro-channel, meter configuration used in an embodiment of a microfluidic analysis system according to the present invention.

18 is a schematic diagram of another position electrode, micro-channel, meter configuration used in an embodiment of a microfluidic analysis system according to the present invention.

FIG. 19 is a schematic diagram of an equivalent electrical circuit for part of the configuration of FIG. 18. FIG.

20 is a schematic diagram of another position electrode, micro-channel, meter configuration used in an embodiment of a microfluidic analysis system according to the present invention.

FIG. 21 is a plot of admittance vs. bolus number. FIG.

The present invention generally relates to analytical devices, and more particularly to microfluidic analysis systems.

In an analysis device based on a liquid sample (ie, a fluid analysis device), in order to obtain a reliable analysis result, the essential liquid sample must be controlled with high precision and high accuracy. This control should be particularly ensured for “microfluidic” analytical devices that use a small amount of liquid, for example a volume of liquid sample corresponding to 10 nanoliters to 10 microliters. In the microfluidic analysis device, the liquid sample is typically stored and transported in a micro-channel having a size of, for example, approximately 10 micrometers to 500 micrometers.

Control of small volumes of liquid samples (ie transport, position detection, flow rate determination and / or volume determination) within the micro-channels can include various assays, including determination of glucose concentrations in interstitial fluids (ISFs). It can be essential to the performance of the process. For example, obtaining reliable results may require information about the liquid sample location to ensure that the liquid sample arrives at the detection zone before the analysis begins. However, relatively small amounts of liquid samples and micro-channels in microfluidic analysis devices make this control difficult.

In the context of an analytical system for blood glucose monitoring, continuous or semi-continuous monitoring systems and methods are characterized by the system and method of blood glucose concentration trends, the effects of food and drugs on blood glucose levels, and the overall blood sugar control of the user. It is advantageous in that it provides enhanced observations regarding glycemic control. The challenge of a continuous or semicontinuous blood glucose monitoring system is that only a small amount of liquid sample (ie, about 250 nanoliter ISF liquid sample) is generally applicable for blood glucose concentration measurements. In addition, it is difficult to transport a small amount of liquid from the target point to the in vivo blood glucose monitor, at a controlled flow rate, and in a manner that provides information about the location and total flow rate of the extracted fluid.

Therefore, there is a need in the art for microfluidic analysis systems that control small amounts of liquid samples and / or alleviate the problems described above.

The microfluidic analysis system according to an embodiment of the present invention enables control of small amounts of liquid samples, or alleviates the problems described above.

A microfluidic analysis system for monitoring analyte (ie, blood glucose) in a liquid sample (ie, ISF), according to an embodiment of the present invention, includes at least one micro-channel for receiving and moving a liquid sample. And an analysis module having at least one analyte sensor and at least one position electrode for measuring the analyte in the liquid sample. The sample sensor (s) and position electrode (s) are in operative communication with the micro-channels.

The microfluidic analysis system also includes a meter configured to measure the electrical properties (ie, impedance or resistance) of the position electrode (s). For example, the meter may measure electrical characteristics (ie, resistance) between both ends of a single position electrode or measure electrical characteristics (ie, impedance) between two position electrodes.

In addition, in an embodiment of a microfluidic analysis system according to an embodiment of the present invention, the measured electrical properties depend on the position of the liquid sample in the micro-channel in operative communication with the position electrode where the electrical properties are measured. For example, the change in measured impedance depends on the front position of the delivery liquid sample in the micro-channel relative to one or more position electrodes.

Since the microfluidic analysis device according to the embodiment of the present invention includes a measuring device for measuring an electrical property depending on the position of the liquid sample in the micro-channel, the measurement includes accurate liquid sample position detection and liquid sample flow rate determination. And / or liquid sample flow rate determination.

A better understanding of the features and advantages of the present invention may be obtained by reference to the following detailed description describing the illustrated embodiments.

1 through 4 illustrate a microfluidic analysis system 100 for determining analyte in a liquid sample (detecting analyte and / or measuring concentration of analyte) according to an embodiment of the present invention.

The microfluidic analysis system 100 comprises a micro-channel 104 for receiving and transporting a liquid sample (i.e., an ISF sample extracted from skin tissue at a target location) and a sample (i.e., sugar) from the liquid sample. And an analysis module 102 having an analyte sample 106 (ie, an electrochemical analyte or an optical analyte sensor) for measurement, and first and second position electrodes 108, 110. 1-4, the micro-channel 104 includes a pre-sensor micro-channel portion 104a and a post-sensor micro-channel portion 104b. . The microfluidic analysis system 100 also includes a sensor chamber 105, in which an analytical sample sensor 106 is disposed.

The microfluidic analysis system 100 further includes a meter 112 for measuring the impedance between the first position electrode 108 and the second position electrode 110, wherein the measured impedance is micro-channel. At 104 the state is dependent upon the position of the liquid specimen (not shown in FIGS. 1-4).

In general, measuring impedance or ohmic resistance between position electrodes in an embodiment of the present invention can be accomplished by applying a voltage between them and measuring the resulting current. One of the constant voltage or the alternating voltage is applied between the position sensors, and the generated direct current (DC) or alternating current (AC) is respectively measured. The generated direct current or alternating current can then be used to calculate impedance or ohmic resistance. In addition, one of ordinary skill in the art (hereinafter, skilled in the art) is aware that impedance measurement can measure ohmic drop (i.e. resistance in ohms [R], or voltage / current) and capacitance (farad capacitance or It will be appreciated that it may include measuring coulombs / voltage). In practice, the impedance can be measured, for example, by applying an alternating current to the position electrode (s) and consequently measuring the current. At different frequencies of alternating current, one of the effects of resistance or capacitance can act predominantly in determining the measured impedance. Pure resistive elements predominately work at low frequencies, while pure capacitive elements may predominately work at high frequencies. To distinguish between resistance or capacitive elements, the phase difference between the applied alternating current and the measured resulting current can be determined. If the phase change is zero, the purely resistive element prevails. If the phase change indicates that the current is sagging with respect to the voltage, the capacitive component is important. Therefore, it is beneficial to measure the resistance, or the combination of resistance and capacitance, because it depends on the frequency of the alternating current and the position electrode configuration.

In the embodiment of FIGS. 1-4, impedance measurement can be made, for example, by applying an alternating voltage between the first position electrode 108 and the second position electrode 110 and measuring the alternating current as a result. The first position electrode 108 and the second position electrode 110 (with a material (ie, air or liquid sample) inside the micro-channel 104 between the first position electrode and the second position electrode, and Since it is part of a capacitor (with a layer) that can separate the position electrode from direct contact with these materials, the measured current can be used to calculate the impedance. The presence or absence of a liquid sample in the micro-channel 104 between the first and second position electrodes will affect the measured current and impedance.

The frequency and amplitude of the alternating voltage applied between the first and second position electrodes can be predetermined such that the presence of a liquid sample between the first and second position electrodes can be detected as a marked increase in the measured current. have.

For impedance and resistance measurements, the magnitude of the applied voltage may be in the range of, for example, about 10 mv to 2 V for the ISF liquid sample and the carbon-based or silver-based ink position electrode environment. The upper and lower limits of the applied voltage range depend on the onset of electrolysis or electrochemical decomposition of the liquid sample. In an environment where an alternating voltage is used, the alternating voltage is applied at a frequency that, for example, can cause negligible net change in the liquid sample in some electrochemical reaction. This frequency range can be about 10 Hz to 100 kHz, where the voltage waveform is symmetric about 0 Volts (ie, the RMS value of the AC voltage is approximately 0).

As shown schematically in FIG. 1, the sample sensor 106, the first position electrode 108 and the second position electrode 110 are each in operative communication with a micro-channel. The position electrodes used in the embodiments of the present invention are conductive materials commonly used as analytical electrode materials, which are known to those skilled in the art, and in particular flexible circuits, photolithographic manufacturing techniques, screen printing. It should be noted that it may be formed of any suitable conductive material, including conductive materials known to be suitable for use in screen printing and flexo-printing techniques. Suitable conductive materials include, for example, carbon, noble metals (ie gold, platinum and palladium), noble metal alloys, conductive potential-forming metal oxides and metal salts. Include. The position electrode may be formed from a conductive silver ink such as, for example, Electrodag 418 SS, which is a commercially available conductive silver ink.

In the embodiment of FIGS. 1-4, the analysis module 102 includes a mold plug 114, a micro-channel 116, and a thin film layer 118 (shown separately in FIGS. 2, 3, and 4, respectively). Additionally included. Analysis module 102 may be configured, for example, by connecting micro-channel disk 116 to thin film layer 118 and mold plug 114.

The mold plug 114 includes an inlet channel 120 and a registration pole 122. The micro-channel disk 116 is configured to define the liquid sample waste reservoir 124 (with the thin layer 118) as well as the micro-channel 104 and the sensor chamber 105 described above. In addition, the micro-channel disc 116 includes a registration hole 126 (eg, as shown in FIG. 3).

The thin film layer 118 includes an access hole 128, a membrane valve 130, and the analytical sample sensor 106 and the first position electrode (described above in the embodiments of FIGS. 1 to 4). 108 and a second position electrode 110.

The micro-channel 104 is perpendicular to the flow direction of the fluid and has a cross-sectional size (ie, in height and width) that ranges from about 10 micrometers to about 500 micrometers. Typical liquid sample volumes to be handled in the micro-channel (s) of an embodiment of the present invention range from about 10 nanoliters to about 10 microliters. In this regard, the term “handled” refers to the liquid sample volume (separated volume in the range of 50 nanoliters to 250 nanoliters) extracted and sequestered at the target location and the minimum liquid sample volume required for the analyte sensor. (E.g., 50 nanoliters) and those not limited to the total volume of liquid sample (e.g., approximately 10 microliters total volume) to be delivered through the micro-channel during the useful lifetime of the microfluidic analysis system. Is involved in the transport of various liquid sample volumes.

The registration pawl 122 of the mold plug 114 is used to ensure proper alignment (ie registration) of the mold plug 114 and the micro-channel disk 116 during the production of the microfluidic analysis system 100. For example, this arrangement allows the analytical sample sensor 106 to be effectively aligned with the sensor chamber 105 and the first and second position electrodes 108 and 110 are arranged after the micro-channel portion (sensor). Ensure that it is aligned with 104b). During the production, the thin film layer 118 may be aligned with the micro-channel disk 116 using registration properties included in the thin film layer 118 and / or the micro-channel disk 116 or by optical identification. Can be.

The registration hole 126 of the micro-channel disk 116 is shown to take the shape of a semicircle and extend through the entirety of the micro-channel 116. The registration pawls 122 are provided in the micro-channels to take a shape and size complementary to the registration holes 126, so that they firmly engage with the mold plug 114 as shown in FIG. 1. The use of semicircles for both the registration hole 126 and the registration pole 122 advantageously limits the degree of freedom of rotation of the mold plug 114 and the micro-channel disk 116 coupling. It should be noted that alternative forms other than the semicircular form may also be used.

Although not shown in FIGS. 1-4, the thin film layer 118 electrically connects the sample sensor 106 to an external device (such as a local controller module described below with respect to FIG. 5) and the first position electrode. Electrical connection for electrically connecting 108 and second position electrode 110 to meter 112. Such electrical connections include, for example, conductive traces and electrical contact pads.

The liquid sample (ie, ISF sample) is conveyed to the inlet channel 120 by appropriate means, such as a sampling module described below with respect to FIG. 5. The flow of liquid sample through the inlet channel 120 is controlled by the membrane valve 130. It should be noted that other types of valves other than the membrane valve may be used, which are well known to those skilled in the art.

In the embodiment of FIG. 1, the membrane valve 130 is deformable and is made of an elastic material in the form of a dome. When the membrane valve 130 is in an undeformed state, the liquid sample can flow through the membrane valve 130 and fill the micro-channel portion 104a before the sensor. However, when the membrane valve 130 is initially deformed (eg, by pressure through the connecting hole 128), the inlet channel 120 is shut off and the flow of liquid sample therethrough is stopped. In addition, with further modification of the membrane valve 130, the liquid sample is pushed into the sensor chamber 105 through the micro-channel portion 104a before the sensor. The movement of the liquid sample through the membrane valve (i.e., from the inlet channel 120 to the pre-sensor micro-channel portion 104a) can be controlled by the amount of pressure applied when the membrane valve is deformed. Typical liquid sample flow rates entering the micro-channels range from about 10 nanoliters per minute to about 1000 nanoliters per minute.

The first position electrodes 108 and the second position electrodes 110 together with the meter 112 are positioned of the liquid specimen inside the micro-electrode 104 to assist in controlling the deformation of the membrane valve 130. And the flow rate of the liquid sample and / or the volume of the extracted liquid sample. It is beneficial to determine the liquid sample position to ascertain when the minimum amount of liquid sample is collected with the analysis module 102 to initiate the sample determination. The membrane also facilitates semi-continuously interrupted flow measurement (measured with a temporarily suspended liquid sample flow, which is not a continuous measurement, but a predetermined number of measurements per hour [typically 4-10 measurements per hour]). In order to control the valve 130, it is beneficial to determine the liquid sample flow rate and / or the total amount of liquid sample introduced into the microfluidic analysis system 100 over a predetermined time period. In addition, determining the liquid sample flow rate and the total amount of liquid sample can slow down the compensation of the sensor. The sample sensor 106 may also be sensitive to flow rate. Therefore, the use of the first position electrode, the second position electrode, and the meter 112 allows the system 100 to more accurately determine the analyte over an extended period of time, for example about eight hours.

In the embodiment of FIGS. 1-4, the analyte sample 106 is disposed inside the sensor chamber 105. The analytical sample sensor 106 may be any suitable sensor known to those skilled in the art. For environments where the analyte of interest is sugar, the analyte sample 106 may be an electrochemical sugar sensor that measures a current proportional to the sugar concentration. In particular, the sample sensor 106 measures current under, for example, suspended flow conditions (i.e., when the flow rate is zero or close to during measurement) and this sugar is electrochemically consumed inside the sensor chamber 105. It can be a sugar sensor. Examples of analytical sample sensors that can be used in embodiments of the present invention include, but are not limited to, electrochemically-based analytical sample sensors and photometric-based analytical sample sensors. Electrochemical based analytical sample sensors include, for example, amperometric, potentiometric, and coulometric analytical sample sensors. Optical measurement based analytical sample sensors include, for example, transmission, reflection, colorimetric, fluorometric, scattering and absorbance analysis sample sensors.

After the analytical sample in the liquid sample is determined by the analyte sensor 106, the liquid sample is transferred to the micro-channel portion 104b after the sensor.

Those skilled in the art will appreciate that an analyte sample monitoring system according to an embodiment of the present invention may be used, for example, as a subsystem of several devices. For example, an embodiment according to the present invention may be used as an analysis module of the system 200 shown in FIG. The system 200 is configured to extract a liquid sample of the body (ie, ISF sample) and monitor the analyte (ie, sugar) therefrom. System 200 includes a disposable cartridge 212 (enclosed by a dashed box), a local controller module 214, and a remote control module 216.

In the system 200, the disposable cartridge 212 includes a sampling module 218 for extracting a liquid sample (ie, ISF) from the body (eg, the user's skin layer), and a fluid extracted from the body. An analysis module 220 for measuring an assay sample (ie, sugar) is included. Sampling module 218 may be any suitable sampling module known to those skilled in the art, while analysis module 220 may be a microfluidic analysis system according to an embodiment of the present invention. Examples of suitable sampling modules include International Patent Application No. PCT / GB01 / 05634 (published in International Publication No. 02/49507, June 27, 2002), and US Patent Application No., which is incorporated by reference in its entirety. 10 / 653,023. However, in the system 200, the sampling module 218 is configured for single use because it is a component of the disposable cartridge 212.

As shown in FIG. 6, the sampling module 218 of the system 200 includes an infiltration member 222 ISF sampling module for infiltrating into a target location of the body B to extract the ISF sample. Launching mechanism 224, at least one pressure ring 228. Sampling module 218 is suitable for providing a continuous or semi-continuous flow of ISF to analysis system 220 for monitoring (ie, concentration measurement) of analyte (such as sugar) in the ISF sample.

While using the system 200, the penetrating member 222 is inserted into the target position (ie, penetrates through the target position) by actuation of the starting structure 224. To extract the ISF sample from the skin layer of the user, the penetrating member 222 may be inserted to a maximum insertion depth, for example, in the range of 1.5 mm to 3 mm. In addition, the penetrating member 222 may be configured to optimize the extraction of the ISF sample in a continuous or semi-continuous manner. In this regard, the penetrating member 222 is, for example, a thin-wall stainless steel noodle with a gauge 25 and a bent tip (not shown in FIGS. 5 and 6). and a support of the bent tip is disposed between the tip of the needle and the end of the needle. Needles suitable for use as penetrating members are described in US patent application Ser. No. 10 / 185,605 (published in US Patent Publication No. 2003/0060784, issued March 7, 2003). In addition, further details about the system 200 are present in US patent application Ser. No. 10 / 718,818.

1 to 4, the first position electrode 108 and the second position electrode 112 are such that the two position electrodes are present downstream of the analyte sample 106 with respect to the micro-channel 104. It is composed. However, other suitable configurations can be applied. For example, FIG. 7 is a schematic diagram of a configuration 300 used in an embodiment of a microfluidic analysis system according to the present invention, consisting of a position electrode, a micro-channel, an analyte sensor, and a meter. The configuration 300 includes a first position electrode 302, a second position electrode 312, an electrical impedance meter 306, a timer 308, a micro-channel 310 and an analyte sample sensor 312. do. In the configuration of FIG. 7, the wavy lines are a liquid sample (ie, ISF, blood, urine, plasma, serum, buffer or reagent liquid) inside the micro-channel 310. Sample).

The configuration 300 can be used to determine the location or flow rate of a liquid sample in the micro-channel 310. In the configuration of FIG. 7, the analyte sample sensor 312 is positioned between the first position electrode 302 and the second position electrode 304. The electrical impedance meter 306 is suitable for measuring the electrical impedance between the first position electrode 302 and the second position electrode 304. Such a measurement can be made, for example, by applying a power source to apply a direct current or alternating voltage between the first position electrode 302 and the second position electrode 304, thereby forming a liquid sample inside the micro-channel. Impedance between the first position electrode 302 and the second position electrode 304, generated by the conductive path, can be measured, which is implemented as a signal indication of the presence of a liquid sample.

In addition, when the electrical impedance meter 306 measures a change in impedance due to the presence of a liquid sample between the first position electrode and the second position electrode, liquid first appears between the first position electrode and the second position electrode. A signal can be passed to the timer 308 to record one time. When the measured impedance indicates that the liquid sample has reached the second position electrode, another signal can be sent to the timer 308. The difference between the time that the liquid sample first appeared between the first position electrode and the second position electrode and the time when the liquid sample reached the second position electrode is the flow rate of the liquid sample (between the first position electrode and the second position electrode). Can be used to determine if the information on the volume of the micro-channel is given). In addition, information about the flow rate of the liquid sample and / or the position of the liquid sample can be used to determine the total amount of the entire liquid sample. In addition, a signal indicative of the position in time when the liquid specimen has reached the second position electrode 304 may be used by the local control module (ie, the local control module of FIG. 5) for use in determining an appropriate deformation state for the membrane valve 130. 214).

8A is a schematic cross-sectional view of how a position electrode can be in operative communication with a micro-channel in an embodiment of a microfluidic analysis system according to the present invention. 8A shows the micro-channel 350 (shown in cross section), the micro-channel disk 352, the position electrode 354, the thin film layer 356, and the meter 358. In the configuration of FIG. 8A, the position electrode 354 is in operative communication with the micro-channel 350 such that the surface 360 of the position electrode 354 is wavy in the micro-channel 350 (FIG. 8A). Exposed to a liquid sample).

In the embodiment of FIG. 8A (and other embodiments of the present invention), the micro-channel disk 352 and the thin film layer 356 may be formed of, for example, a polymeric insulating material (ie, polystyrene, silicon rubber, PMMA, Polycarbonate or PEEK) and electrically insulating materials such as glass and other non-molecular insulating materials.

FIG. 8B is a schematic cross-sectional view (using reference numerals such as FIG. 8A) showing another way in which a position electrode can be in operative communication with a micro-channel in an embodiment of a microfluidic analysis system according to the present invention. FIG. FIG. 8B shows the micro-channel 350 (shown in cross section), the micro-channel disk 352, the position electrode 354, the thin film layer 356 and the meter 358. In the configuration of FIG. 8B, the position electrode 354 is in operative communication with the micro-channel 350, but is separated from the micro-channel 350 by a portion of the insulating layer, ie, the thin film layer. The advantage of the scheme shown in FIG. 8B is that there is no direct contact between the liquid sample in the micro-channel 350 and the position sensor 354, resulting in any electrolysis or electrochemical of the liquid sample due to the position electrode 354. No decomposition can occur.

9 is a conceptual diagram of a configuration 400 consisting of other micro-channels, analyte sensors, and position electrodes used in embodiments of the microfluidic analysis system according to the present invention. The configuration 400 includes a first position sensor 402, a second position sensor 404, an electrical impedance meter 406, a timer 408, and an analyte sample sensor 412. In the configuration of FIG. 9, the wavy lines show the liquid sample (ie, ISF, blood, urine, plasma, serum, buffer or reagent liquid sample) inside the micro-channel 410.

In the embodiment of FIG. 9, both the first position electrode 402 and the sample sensor 412 are in operative communication with a local control module 214. In this manner, the first position electrode can serve as a position electrode and as a reference electrode for the analyte sensor 412 (assuming that the analyte sensor 412 is an electrochemically based analyte sample sensor). In addition, it should be noted that the electrical impedance meter 406 and the timer 408 can be incorporated into the local control module 214.

An advantage of the arrangement of FIG. 9 is the reduced complexity achieved by using the first position electrode as a reference electrode for the position electrode and the analyte sensor 412. In the configuration of FIG. 9, the first position electrode 402 can be produced, for example, with a material that forms a stable potential between the first position electrode and the liquid sample. In an environment where the liquid sample is an ISF sample, the first position electrode may be composed of silver / silver chloride (Ag / AgCl).

10 is a schematic diagram of a configuration 450 consisting of another position electrode, a micro-channel, an analyte sensor, and a meter, used in an embodiment of a microfluidic analysis system according to the present invention. The configuration 450 includes a first position electrode 452, a second position electrode 454, and a third position electrode 456, respectively, and include an analytical sample sensor 458, an electrical impedance measuring instrument 460, and a timer. 462 and micro-channel 464. The electrical impedance meter 460 is configured to measure electrical impedance between any one of the first position electrode, the second position electrode, and the third position electrode.

The configuration 450 differs from other configurations 300 and 400 in that the configuration 450 includes three position electrodes. Inclusion of three position electrodes provides improved ability to detect the exact position and flow rate of the liquid sample inside the micro-channel 464. For example, the use of two position electrodes enables detection of a single bolus (ie, the volume maintained at the micro-electrode between two position electrodes). However, the use of three (or more) position electrodes enables the detection of several boluses when the liquid sample passes through three (or more) position electrodes sequentially.

11 is a configuration consisting of a position electrode, a micro-channel (consisting of a main micro-channel and two branch micro-channels), an analyte sensor and a meter, used in an embodiment of a microfluidic analysis system according to the present invention. 500 is a schematic diagram. The configuration 500 includes a micro-channel consisting of a main micro-channel 502, a first branch micro-channel 504 and a second branch micro-channel 506. The configuration 500 also includes a first position electrode (operationally in communication with the main micro-channel 502), a second position electrode 510 (operationally in communication with the first branch micro-channel) and ( A second position electrode) in operative communication with the two branch micro-channel 506.

In addition, the configuration 500 includes a second analysis (operationally in communication with the first branch micro-channel 504) and a second analysis (operationally in communication with the second branch micro-channel). A sample sensor 516, a meter 518, and a timer 520. The meter 518 is configured to measure electrical characteristics (ie, impedance) between the first position electrode and any one of the second position electrode and the third position electrode.

The configuration 500 includes liquid processing means for respectively directing a liquid sample from the main micro-channel 502 to either one of the first branch micro-channel 504 and the second branch micro-channel 506. It is contemplated to use the device. Examples of genital liquid treatment means include, but are not limited to, active valves, passive valves, capillary breaks, air pressure barriers, and hydrophobic patches. It doesn't happen.

The configuration 500 may include the first branch micro-channel 504 or the first position electrode and the first position electrode (by using the meter 518 to measure electrical characteristics between the first position electrode and the second position electrode). By using the meter 518 to measure the electrical properties between the three position electrodes) in either of the second branch micro-channels 506. Such detection (s) may be used for control of liquid sample flow and determination of analyte in the liquid sample by either the first sample sensor 514 or the second sample sensor 516.

11 is a configuration consisting of a different position electrode, a micro-channel (composed of a main micro-channel and two branch micro-channels), an analyte sample sensor and a meter, used in an embodiment of a microfluidic analysis system according to the present invention Schematic diagram for 550. The configuration 550 includes a micro-channel consisting of a main micro-channel 552, a first branch micro-channel 554 and a second branch micro-channel 556. The configuration 550 also includes a first position electrode 558 and a second position electrode 560 (operationally in communication with the second branch micro-channel 554), and the second branch position micro-channel ( A third position electrode 562 and a fourth position electrode 564) in operative communication with 556.

In addition, the configuration 550 may be configured to communicate with the first analyte sensor 566 (operationally in communication with the first branch micro-channel 554) (in operation with the second branch micro-channel 556). A second analysis sample sensor 568, measuring instrument 570, timer 572 is included. The meter 570 is configured to measure an electrical characteristic (ie, impedance) between any one of the first position electrode and the second position electrode and any one of the third position electrode and the fourth position electrode.

The configuration 550 includes liquid processing means for respectively directing a liquid sample from the main micro-channel 552 to either one of the first branch micro-channel 554 and the second branch micro-channel 556. It is contemplated to use the device. Examples of such liquid processing means include, but are not limited to, active valves, passive valves, capillary brakes, pneumatic barriers and hydrophobic patches.

The configuration 550 may comprise a first branch micro-channel 554 (by using the meter 570 to measure electrical characteristics between the first position electrode 558 and the second position electrode 560) or ( By using the meter 570 to measure the electrical properties between the first and third position electrodes), which may be used to detect the position of the liquid sample in either of the second branch micro-channels 556. Such detection (s) may be used for control of liquid sample flow and determination of analyte in a liquid sample by either the first sample sensor 566 or the second sample sensor 568. The advantage of the configuration 550 is that the first position electrode and the second position electrode (as well as the third position electrode and the fourth position electrode) are accurate in that they are highly accurate in high electrical properties (ie, relatively high impedance) between them. It can be located relatively close to each other to allow measurements.

13 is a schematic diagram of a configuration 600 consisting of a position electrode, a micro-channel and a meter, used in an embodiment of a microfluidic analysis system according to the present invention. FIG. 14 is a schematic diagram of an equivalent electrical circuit for a portion of the configuration 600 of FIG. 13.

The configuration 600 includes a first position electrode 602 and a second position electrode 604 in an interdigitated configuration. The configuration 600 also includes a micro-channel 606 and a meter 608. The first position electrode 602 and the second position electrode 604 are arranged in a plurality of arranged in parallel with each other and in succession (ie, in a "finger-shaped" manner alternately as shown in Figure 13). Each electrode part is provided. For the purpose of illustration, four electrode portions (602a, 604b, respectively) of the first position electrode 602 and the second position electrode 604 are shown in FIG. The interdigitated electrode portion may also be referred to as a "finger".

The position electrode of the embodiment of the present invention, and the gap therebetween can be made to an appropriate size. Advantageously, the interdigitated manner can be used in sizes (ie, W _g , W _{e in} FIG. 13) that enable measurable electrical properties of relatively small liquid samples.

In the configuration 600, each "finger" independently has a width W _e corresponding to, for example, in the range of about 1 micrometer to about 1500 micrometers. Separation between electrode “fingers” (W _g ) may exist, for example, in a range between about 0.1 millimeters and about 15 millimeters. The thickness of the position electrode is sufficient to support the desired current. Exemplary thicknesses can range, for example, from about 1 micrometer to about 100 micrometers.

A chamfered approach, such as the configuration 600, can be used to detect liquid sample bolus flowing through the micro-channel 606. This bolus has a predetermined volume (such as 250 nanoliters) defined by the height and width of the micro-channel 606 and the distance W _g . For example, if the micro-channel 606 has a height and width having a size of about 250 microns, the width W _e is about 0.5 millimeters and the distance W _g is about 4 millimeters, In the absence of any liquid sample filling the void between any of the fingers of the other position electrode 604, the resistance between the first position electrode 602 and the second position electrode 604 becomes in principle infinite. However, if the ISF liquid sample fills (fills) the micro-channel 606 between the finger of the first position electrode and the finger of the second position electrode (the environment shown by the wavy lines in FIG. 13), the measurement Total resistance (R ₁ ) decreases to about 37 kiloohms of liquid resistance.

In the configuration 600, the resistance R _e of each finger is less than the total resistance R ₁ with a coefficient corresponding to at least about 10. When the micro-channel 606 is additionally filled with a liquid sample, the measured total resistance R _T between the first position electrode 602 and the second position electrode 604 further decreases. The decrease in the measured total resistance (R _T ) is equal to

The configuration 600 is particularly useful when R _e is much smaller than R ₁ .

In the configuration 600, the micro-channel 606 is shown in a state of passing (ie being in operative communication) with each electrode finger 602a only once. However, the micro-channel 606 may alternatively have a serpentine configuration, such that the micro-channel 606 may pass through each electrode finger 602a over multiple. This configuration can enhance the ability to easily interpret relatively small liquid sample volumes (ie, liquid sample volumes of less than 5 nanoliters).

15 is a schematic diagram of a configuration 650 consisting of a position electrode, a micro-channel and a meter, used in an embodiment of a microfluidic analysis system according to the present invention. FIG. 16 is a schematic diagram of an equivalent electrical circuit for part of the configuration of FIG. 15.

The configuration 650 includes a comb-shaped single position electrode 652 with eight “fingers”, a micro-channel 654 and a meter 656. Electrode finger 652a serves to define an electrode segment with resistance R _e between the fingers (as shown in FIG. 16). It should be noted that the sizes W _g , W _e of FIG. 16 may be as described above for the previous configuration 600.

If there is no liquid sample in the micro-channel 654 between any of the eight fingers 652a, the measured total resistance of the position electrode 652 is the respective electrode segment resistance R _e (ie, Resistance to all electrode elements). However, once the liquid sample fills the micro-channel 654 between the fingers 652a, the measured total resistance R _T decreases because R ₁ is generated parallel to R _e (see FIG. 16). Note that for the configuration 650, each electrode segment resistance R _e is much larger than R ₁ , preferably with a coefficient of at least 10.

17 is a schematic diagram of a configuration 700 consisting of position electrodes, micro-channels and a meter, used in a microfluidic analysis system according to the present invention. The configuration 700 includes a curved single position electrode 702, a micro-channel 704, and a meter 706.

It should be noted that the sizes W _g , W _e in FIG. 16 may be the same as described above for the previous configuration 600.

18 is a schematic diagram of a configuration 750 consisting of a position electrode, a micro-channel and a meter, used in an embodiment of a microfluidic analysis system according to the present invention. FIG. 19 is a schematic diagram of an equivalent electrical circuit for a portion of configuration 750 of FIG. 18.

The configuration 750 includes a position electrode 752, a micro-channel 754, a bypass electrode 756, and a meter 758. The position electrode 752 is a single comb-shaped electrode having eight "fingers" 752a. Electrode finger 752a serves to define an electrode segment with resistance R _e between the electrode fingers (as shown in FIG. 10). It should be noted that the sizes W _g , W _e in FIG. 18 may be the same as described above for other configurations 600.

In the absence of a liquid sample, the auxiliary electrode 756 is in an electrically floating state. However, when a liquid sample is present between two consecutive electrode fingers 752a, the auxiliary electrode 756 becomes part of the circuit shown in FIG. 19 and characterized by the resistance R _b .

Assuming that the resistance R _b is much smaller than R ₁ '(ie, the resistance of the liquid sample between the electrode finger and the auxiliary electrode), more current will flow through the auxiliary electrode than the liquid sample. Therefore, the configuration 750 is advantageous when used in conjunction with a high resistance liquid sample because the auxiliary electrode 756 effectively reduces R _T as shown in FIG. 19. In addition, once knowledge of the present invention, one of ordinary skill in the art will appreciate that the auxiliary electrode may have a variety of electrode configurations between the position electrodes or between the electrode fingers in order to reduce the overall resistance measured in the presence of a relatively low liquid sample. For example, it will be appreciated that the arrangement may be similarly shown in FIGS. 7 and 9 to 13 and 17.

20 is a schematic diagram of a configuration 800 consisting of a position electrode, a micro-channel, a meter, used in an embodiment of a microfluidic analysis system according to the present invention. The configuration 800 includes a position electrode 802, a micro-channel 804 and a meter 806. Meter 806 is configured to measure the continuously varying electrical properties of position electrode 802 as the liquid sample (shown as wavy lines in FIG. 20) passes through micro-channel 804.

Example

A shaved configuration similar to FIG. 13 was tested using phosphate buffer as a liquid sample. The 1st position electrode and the 2nd position electrode of the said structure were formed with silver / silver chloride using screen printing technique. In addition, the first position electrode and the second position electrode were separated by a distance W _g of 4 millimeters.

A potential waveform with a frequency of 0.25 MHz, amplitude of +/- 0.1 volts and RMS of 0 volts was applied between the first and second position electrodes. Based on the resulting current between the first position electrode and the second position electrode, the measured total resistance R _T and the measured admittance were calculated (note that A _T = 1 / R _T ). 21 shows that the measured total admittance A _T increases linearly as a continuous liquid sample bolus passes through each electrode of the above configuration.

21 shows that each successive bolus was detected as a change in admittance. Hence, the bolus can calculate the number by, for example, monitoring a spike on the measured impedance signal versus the derivative of the signal.

It should be understood that various alternatives to the invention described herein may be used in the practice of the invention. The following claims define the scope of the invention and the structures within the scope of these claims and their equivalents are intended to be included herein.

The microfluidic analysis system according to the invention allows a relatively small amount of liquid to be conveyed from the target point to the monitoring device, at a controlled flow rate and in a manner in which information about the location and total flow rate of the extracted fluid is provided. It enables accurate and reliable control of liquid samples.

Claims (16)

In a microfluidic analysis system for monitoring analyte in a liquid sample, At least one micro-channel for receiving and transporting a liquid sample; At least one analyte sensor for measuring analytes in a liquid sample, at least one analyte sensor, each analyte sensor in operative communication with a micro-channel; An analysis module comprising at least one position electrode in which each position electrode is in operative communication with the micro-channel; A meter configured to measure the electrical properties of the at least one position electrode, the electrical properties depending on the position of the liquid specimen in the micro-channel in operative communication with the at least one position electrode on which the electrical properties are to be measured. Microfluidic analysis systems. The microfluidic analysis system of claim 1, further comprising a timer in operative communication with the meter. The microfluidic analysis system of claim 1, wherein the position electrode is in operative communication with the micro-channel such that the surface of the position electrode is exposed to the micro-channel. The microfluidic analysis system of claim 1, wherein the location electrode is in operative communication with the micro-channel such that an insulating layer separates the location electrode and the micro-channel. 2. The apparatus of claim 1, wherein the at least one position electrode comprises a first position electrode and a second position electrode, the first position electrode and the second position electrode being in operative communication with a first micro-channel, And the meter is configured to measure electrical characteristics between the first position electrode and the second position electrode. The microfluidic analysis system of claim 5, wherein the analyte sample sensor is disposed between the first position electrode and the second position electrode. 6. The microfluidic analysis system of claim 5, wherein the first position electrode and the second position electrode are downstream of the analyte sample sensor. 6. The microfluidic analysis system of claim 5, wherein the electrical characteristic is at least one of an impedance between the first position electrode and the second position electrode and a resistance between the first position electrode and the second position electrode. The microfluidic analysis system of claim 1, wherein the at least one position electrode is in operative communication with the analyte sample. 6. The apparatus of claim 5, further comprising a third position electrode in operative communication with the first position electrode, wherein the meter comprises an electrical device between any one of the first position electrode, the second position electrode, and the third position electrode. Microfluidic analysis system configured to measure characteristics. The microfluidic analysis system of claim 1, wherein the micro-channel comprises at least one main micro-channel and at least a first branch micro-channel and a second branch micro-channel. 12. The method of claim 11, wherein the at least one position electrode comprises at least one position electrode in the main micro-channel, at least one position electrode in a first branch micro-channel, and at least in a second branch micro-channel. One position electrode, And the measuring device measures electrical characteristics between the position electrode of the main micro-channel, the position electrode of the first branch micro-channel and the position electrode of the second branch micro-channel. 12. The method of claim 11, wherein the at least one location electrode comprises at least two location electrodes in a first branch micro-channel and at least two location electrodes in a second branch micro-channel, Wherein the meter measures electrical characteristics between two position electrodes of the first branch micro-channel or between two position electrodes of the second branch micro-channel. 12. The microfluidic analysis system of claim 11, wherein the at least one position electrode comprises a first position electrode and a second position electrode configured in the shape of a rib. 12. The microfluidic analysis system of claim 11, wherein said at least one position electrode is a serpentine position electrode. The microfluidic analysis system of claim 1, further comprising an auxiliary electrode.

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